A kinetic assessment of the C-elegans amyloid disaggregation activity enables uncoupling of disassembly and proteolysis

Protein aggregation is a common feature of late onset neurodegenerative disorders, including Alzheimer's disease. In Alzheimer's disease, misassembly of the A beta peptide is genetically linked to proteotoxicity associated with disease etiology. A reduction in A beta proteotoxicity is accomplished, in part, by the previously reported All disaggregation and proteolysis activities-under partial control of heat shock factor 1, a transcription factor regulating proteostasis in the cytosol and negatively regulated by insulin growth factor signaling. Herein, we report an improved in vitro assay to quantify recombinant fibrillar A beta disaggregation kinetics accomplished by the exogenous application of C. elegans extracts. With this assay we demonstrate that the A beta disaggregation and proteolysis activities of C. elegans are separable. The disaggregation activity found in C. elegans preparations is more heat resistant than the proteolytic activity. A beta disaggregation in the absence of proteolysis was found to be a reversible process. Future discovery of the molecular basis of the disaggregation and proteolysis activities offers the promise of delaying the age-onset proteotoxicity that leads to neurodegeneration in a spectrum of maladies.